Liu Simeng, Liu Huimin, Song Xiaoshuang, Jiang Ailing, Deng Yuchuan, Yang Chengli, Sun Dan, Jiang Kun, Yang Fan, Zheng Yu
State Key Laboratory of Biotherapy/Collaborative Innovation Centre of Biotherapy, West China Hospital, Sichuan University, 17#, Section 3, Ren Min Nan Road, Chengdu, Sichuan, 610041, PR China.
Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.
Nanoscale. 2021 Oct 1;13(37):15789-15803. doi: 10.1039/d1nr04036g.
The immunosuppressive tumor microenvironment has become a formidable obstacle to the treatment of tumors using adoptive T cell therapy, in particular solid tumors. For the purposes of addressing this issue, effector OT-1 CD8T cells conjugated with liposomal immune regulators (CD8-T-LP-CpG/CD8-T-LP-BMS-202) were developed. An anionic liposome formulation was employed to avoid T cell aggregation and prevent unfavorable side-effects. The inclusion of EGCG in the LP-CpG formulation facilitated the formation of compact complexes with poly lysine (PLL) and is thus expected to increase the stability. CD8-T-LP-CpG administered with a median dose of CpG (20 μg per mouse) markedly reduced the frequency of tumor infiltrating polymorphonuclear leukocyte myeloid-derived suppressor cells (PMN-MDSCs) (20-folds), M2-like macrophages (8-folds), regulatory T-cells (Treg) (2.7-folds), and consequently increased the frequency of cytotoxic CD8T cells in tumor-infiltrating lymphocytes (TILs) (2-folds) and splenic effector memory CD8T cells (3-folds) relative to the phosphate buffered saline (PBS) control group. Furthermore, the absolute number of tumor infiltrating lymphocyte subtypes altered followed a consistent trend. The difference remained significant compared to the OT-1 CD8T cells and the drug-loaded liposome combination group. According to imaging of CD8-T-LP-DiD, we assumed that the improvement in regulation of the tumor microenvironment of LP-CpG/LP-BMS-202 was attributed to the enhanced drug transportation to the tumor site aided by tumor-specific OT-1 CD8T cells. In addition, CD8-T-LP-BMS-202 administered with a low dose of BMS-202 (1.5 mg per kg body weight) exerted a dramatically improved therapeutic effect by reducing the tumor infiltrating PMN-MDSCs and M2-like macrophages and the corresponding promoted cytotoxic CD8T cell recruitment in the TILs and effector memory CD8T cells mediated anti-tumor immunity. In summary, immune therapy drugs backpacked onto adoptive T cell therapy provides a feasible strategy to improve the therapeutic effect and could result in future clinical translation.
免疫抑制性肿瘤微环境已成为采用过继性T细胞疗法治疗肿瘤（尤其是实体瘤）的巨大障碍。为了解决这个问题，人们研发了与脂质体免疫调节剂（CD8-T-LP-CpG/CD8-T-LP-BMS-202）偶联的效应性OT-1 CD8 T细胞。采用阴离子脂质体制剂以避免T细胞聚集并防止不良副作用。在LP-CpG制剂中加入表没食子儿茶素没食子酸酯（EGCG）有助于与聚赖氨酸（PLL）形成紧密复合物，因此有望提高稳定性。以中位剂量的CpG（每只小鼠20μg）给药的CD8-T-LP-CpG显著降低了肿瘤浸润性多形核白细胞髓源性抑制细胞（PMN-MDSC）（20倍）、M2样巨噬细胞（8倍）、调节性T细胞（Treg）（2.7倍）的频率，从而相对于磷酸盐缓冲盐水（PBS）对照组，使肿瘤浸润淋巴细胞（TIL）中的细胞毒性CD8 T细胞频率增加了2倍，脾效应记忆CD8 T细胞频率增加了3倍。此外，肿瘤浸润淋巴细胞亚型的绝对数量变化遵循一致趋势。与OT-1 CD8 T细胞和载药脂质体组合组相比，差异仍然显著。根据CD8-T-LP-DiD成像，我们推测LP-CpG/LP-BMS-202对肿瘤微环境调节的改善归因于肿瘤特异性OT-1 CD8 T细胞辅助下药物向肿瘤部位的转运增强。此外，以低剂量的BMS-202（每千克体重1.5mg）给药的CD8-T-LP-BMS-202通过减少肿瘤浸润的PMN-MDSC和M2样巨噬细胞以及相应促进TIL和效应记忆CD8 T细胞介导的抗肿瘤免疫中细胞毒性CD8 T细胞的募集，发挥了显著改善的治疗效果。总之，搭载在过继性T细胞疗法上的免疫治疗药物为提高治疗效果提供了一种可行策略，并可能导致未来的临床转化。
